Pemetrexed, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1Hpyrrolo[2,3-d] pyrimidin-5-yl)ethyl]benzoyl]-L-Glutamic acid (also known as pemetrexed diacid), having the following formula:

is a potent inhibitor of several folate-requiring enzymes and is useful for the treatment of non-small cell lung cancer and mesothelioma. Pemetrexed is available in market under the brand name ALIMTA® with the active ingredient chemically described as L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-disodium salt heptahydrate (“Pemetrexed disodium heptahydrate”). The commercially-available product, ALIMTA®, is supplied as a sterile lyophilized powder available in single-use vials for intravenous infusion.
Active pharmaceutical ingredients (APIs) can be prepared in a variety of different forms, such as, chemical derivatives, solvates, hydrates, co-crystals, or salts. APIs may also be prepared in different solid forms, in that they may be amorphous, may exist as different crystalline polymorphs, and/or in different salvation or hydration states. By varying the form of an API, it is possible to vary the physical properties thereof. For instance, solid forms of an API typically have different solubilities such that a more thermodynamically stable solid form is less soluble than a less thermodynamically stable solid form. Solid forms can also differ in properties such as shelf-life, bioavailability, morphology, vapor pressure, density, color, and compressibility. Accordingly, variation of the solid state of an API is one of many ways to modulate the physical and pharmacological properties thereof.
U.S. Pat. No. 5,344,932 (“the U.S. '932 patent”), which is incorporated herein by reference in its entirety, refers to pemetrexed diacid or a pharmaceutically acceptable salts thereof.
International application publication No. WO 01/14379 A2 (“the WO '379 publication”) describes novel crystalline form of Pemetrexed disodium designated as “Hydrate Form I”. According to WO '379 publication, the term “hydrate” describes crystalline lattice of pemetrexed disodium salt, which can contain variable amounts of water, from about 0.01 to about 3 equivalents of water, depending upon relative humidity in the storage conditions and preferably hydrate Form I contains from about 2 to about 3 equivalents of water, most preferred is 2.4-2.9 equivalents of water. Therefore, the “Hydrate form I” may not be suitable for making the finished dosage form of pemetrexed disodium because of the difficulties encountered due to its disadvantageous properties such as hygroscopic nature, and retaining variable amounts of water based on relative humidity.
U.S. Pat. No. 7,138,521 (“the U.S. '521 patent”) describes that pemetrexed disodium can exist in another crystalline form i.e., a heptahydrate form which is more stable than the previously known 2.5 hydrate and the primary advantages of the heptahydrate crystalline form is stability with respect to the solvent content and stability with respect to growth of related substances. However, according to the U.S. '521 patent, the heptahydrate crystalline form when subjected to elevated temperatures, low humidity and/or vacuum, converts to the 2.5 hydrate crystal form by loss of water. In view of said limitations, the process for the preparation of heptahydrate requires specific critical conditions which are described in Column 3, lines 4-30 of the U.S. '521 patent and one of which is drying under humid nitrogen to remove the acetone content and maintain the desired water content. In view of the above, “heptahydrate crystalline form” may not be well suited for making the finished dosage form of pemetrexed disodium because of the difficulties encountered due to its disadvantageous properties such as polymorphic stability at low humidity and/or vacuum condition and converting to a lower hydrate by loss of water when exposed to elevated temperatures.
In order to overcome the difficulties connected with the hygroscopic nature and polymorphic stability of the known forms of pemetrexed disodium, some research groups focused on discovering new crystalline forms of pemetrexed disodium with better physical parameters.
International application publication No. WO 2011/064256 A1 (“the WO '256 publication”) and Chinese Patent no. 1778802 (“the CN '802 patent”) describe different crystalline form of pemetrexed disodium.
However, the diversity of crystalline forms of pemetrexed disodium may be disadvantageous to keep uniformity of different manufacturing batches and as a consequence to preserve uniformity in the finished dosage form.
In order to overcome the difficulties associated with reported polymorphic forms of pemetrexed disodium, some research groups focused on discovering new crystalline forms of pemetrexed diacid and novel polymorphs of other salts forms of pemetrexed.
International application publication No. WO 2008/021405 A1 (“the WO '405 publication”) and WO2010/031357 A1 (“the WO '357 publication”) describe various crystalline forms of pemetrexed diacid and process for their preparation.
It may be noted that, according to the description provided in the WO '379 publication, there are several disadvantages associated with pemetrexed diacid, for e.g., it is highly toxic requiring special handling measures and equipments and also isolation of the acid requires difficult operation which is time consuming and costly.
Chinese Patent Application No. CN 101033227, CN 10691371 and CN 1,552,713 disclose different new salts of pemetrexed and processes for preparation thereof. However, the polymorphic forms of these salts may not be useful due to their physico chemical properties such as lower solubility.
In order to overcome the disadvantages associated with the reported polymorphic forms of pemetrexed diacid, pemetrexed disodium and the other salts of pemetrexed, the inventors of the present application felt that there is a need to provide novel crystalline forms of pemetrexed tromethamine salts which have improved physical properties and deprived of the disadvantageous associated with known polymorphic forms of pemetrexed diacid, pemetrexed disodium and the other salts of pemetrexed.
The present invention relates to novel crystalline forms of pemetrexed tromethamine salts that are useful for manufacture of pharmaceutical dosage forms and possess one or more properties that provide advantages when used as an API. The present invention also provides processes for preparation of such novel crystalline forms.